FBXL5/SOX2轴影响非小细胞肺癌发生发展的机制研究

Non-small cell lung cancer (NSCLC) is a common malignancy. Identification of key regulatory genes in NSCLC development and progression is of significance for development of effective anticancer therapies. FBXL5 is a F-box protein and downregulated in NSCLC tissues. It is involved in ubiquitination-mediated degradation of human single strand binding protein 1 and can enhance the sensitivity to radiochemotherapy in NSCLC cells. Our prior work has demonstrated that FBXL5 can also interact with SOX2 and promote its degradation and that overexpression of FBXL5 and downregulation of SOX2 causes similar anticancer effects. Therefore, we proposed a hypothesis that FBXL5 exerts its anticancer activity in NSCLC via promotion of SOX2 protein degradation. To test this hypothesis, in this project we aimed to investigate the mechanism for FBXL5-mediated degradation of SOX2 protein, to clarify the roles of the FBXL5/SOX2 axis in NSCLC development and growth and cell stemness, and to identify the key target genes of SOX2 that mediate the anticancer effects of FBXL5 in NSCLC. This project will confirm for the first time the biological significance of the FBXL5-SOX2 interaction in NSCLC cells and provide more insight into the pathogenesis of NSCLC development and progression. This project may offer new therapeutic targets for NSCLC treatment.

非小细胞肺癌（NSCLC）是一种常见恶性肿瘤。鉴定NSCLC发生发展的关键调控基因对于开发有效的治疗方法具有重大意义。FBXL5是一种F-box蛋白，在NSCLC中表达下调，可参与人单链结合蛋白1（hSSB1）泛素化降解以及增强放化疗敏感性。本课题组前期工作证实：FBXL5也可与SOX2蛋白结合并促进后者降解；在NSCLC细胞中过表达FBXL5或下调SOX2可产生类似的抑癌效应。鉴于此，申请者提出一个科学假设：即FBXL5通过调控SOX2蛋白降解行抑癌效应。为了证实该推测，本项目拟研究FBXL5调控SOX2蛋白降解的详细机制，阐明FBXL5/SOX2轴对NSCLC发生、生长以及肿瘤干细胞特性的调控作用，鉴定介导FBXL5抑癌效应的SOX2靶基因。本研究将首次揭示FBXL5与SOX2相互作用在NSCLC中的生物学意义，对认识NSCLC发生发展机制以及确定新的治疗靶点都具有重要价值

肺癌是全球最常见的癌症之一，也是与癌症相关的死亡的主要原因。非小细胞肺癌（NSCLC）约占所有肺癌的85％。由于NSCLC复发和转移的发生率很高，因此其预后较差，5年总生存率不到15％。阐明涉及NSCLC进展的分子机制对于改善治疗效果至关重要，本项目将重点对其进行研究。化疗目前仍然是晚期肺癌最常用的治疗方案之一，但整体预后仍然很差，中位总生存期很短。 . 本研究着重阐明了肺癌发生发展的机制。结果表明 rs2275913和rs12203582多态性会增加中国人群患肺癌的风险，并且与临床病理亚型和吸烟状况相关。miR-516a-5p的低表达是NSCLC患者肿瘤复发的独立预后因子，miR-516a-5p通过靶向HIST3H2A抑制NSCLC细胞的增殖。SIRT6能使Snail去乙酰基化，以防止其被蛋白酶体降解，并促进Snail依赖的KLF4的反式表达，从而导致癌症具有侵袭性。此外，Adjudin通过调节人肺癌细胞中的SIRT3-FOXO3a轴与紫杉醇协同抑制肺癌细胞的生长和转移。这些研究可为肺癌的治疗提供了一些可靠的靶点，有助于提升晚期肺癌病人的生存率。